Lung cancer is the major cause of cancer deaths in the US, and existing therapies fail to treat this disease successfully in the overwhelming majority of cases. Recently, having low levels of let-7, a member of a new class of global gene regulators called microRNAs (miRNAs), was identified as a predictor of a poor outcome in lung cancer patients. In this work we propose to test the hypothesis that the miRNA let-7 is a tumor suppressor in the lung and may be a novel but potentially powerful approach to treat and/or sensitize lung cancer to cytotoxic therapy. In Specific Aim 1 of this proposal we will test the hypothesis that let-7 is indeed a tumor suppressor in the lung and could be used to reverse lung cell growth based on the findings that: 1) In C. elegans over-expression of let-7 can suppress the activating mutations in RAS 2) let-7 suppresses human RAS in vitro and is at low levels in human lung cancer, and 3) let-7 overexpression in vitro and in vivo can reverse lung cell growth (preliminary data). We will further test the hypothesis that let-7 can reduce or reverse the oncogenic effects of activate K-Ras in a mouse model of lung cancer. In Specific Aim 2 we will test the hypothesis that let-7 manipulation can be used to impact the cellular response to cytotoxic therapy. We have previously shown that let-7 is involved in the response to radiotherapy in lung cells, and that let-7 manipulation can impact cell survival post-irradiation. We will further validate the mechanism of these findings, the involvement of let-7 in the response to other cytotoxic therapies, and the potential of impacting lung cancer cell survival post-cytotoxic therapy with let-7 manipulation in vivo in xenograft and mouse models of lung cancer. These studies could be the first steps towards a lung cancer therapy involving let-7. We posit that our analysis of mammalian let-7, which may be a master regulator of human cancer genes, has the potential to drastically improve our understanding of lung cancer. Overall, the work outlines in this proposal should shed light on the mechanisms of lung cancer development and response to therapy, and has the potential to lead to a novel treatment approach for lung cancer patients, currently a clinical group lacking effective therapies. We feel that because our proposed intervention is based upon a natural miRNA-directed cellular process, it has enhanced chance for success with limited toxicity.